DE69531956T2 - IMIDAZOLE DERIVATIVES WITH PROTEIN KINASE, IN PARTICULAR EGF-R TYROSINKINASE, INHIBITING EFFECT - Google Patents
IMIDAZOLE DERIVATIVES WITH PROTEIN KINASE, IN PARTICULAR EGF-R TYROSINKINASE, INHIBITING EFFECT Download PDFInfo
- Publication number
- DE69531956T2 DE69531956T2 DE69531956T DE69531956T DE69531956T2 DE 69531956 T2 DE69531956 T2 DE 69531956T2 DE 69531956 T DE69531956 T DE 69531956T DE 69531956 T DE69531956 T DE 69531956T DE 69531956 T2 DE69531956 T2 DE 69531956T2
- Authority
- DE
- Germany
- Prior art keywords
- imidazol
- chlorophenyl
- compound
- pyridin
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title claims description 3
- 102000001253 Protein Kinase Human genes 0.000 title description 6
- 108060006633 protein kinase Proteins 0.000 title description 6
- 230000002401 inhibitory effect Effects 0.000 title description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- -1 2,4,6-trimethylphenyl Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005594 diketone group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- IFIWNDROKONIBD-UHFFFAOYSA-N 1-[[3-[4-(4-chlorophenyl)-5-pyridin-4-yl-1h-imidazol-2-yl]-2,4,6-trimethylphenyl]methyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CC1=C(C)C=C(C)C(C=2NC(=C(N=2)C=2C=CN=CC=2)C=2C=CC(Cl)=CC=2)=C1C IFIWNDROKONIBD-UHFFFAOYSA-N 0.000 claims description 4
- GFAFNVNPKLTMGT-UHFFFAOYSA-N 4-[2-(2-bromo-6-methylphenyl)-4-(4-fluorophenyl)-1h-imidazol-5-yl]pyridine Chemical compound CC1=CC=CC(Br)=C1C1=NC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 GFAFNVNPKLTMGT-UHFFFAOYSA-N 0.000 claims description 4
- OAOVPBOWCVXFDD-UHFFFAOYSA-N 4-[4-(3-methylphenyl)-2-(2,4,6-trimethylphenyl)-1h-imidazol-5-yl]pyridine Chemical compound CC1=CC=CC(C2=C(N=C(N2)C=2C(=CC(C)=CC=2C)C)C=2C=CN=CC=2)=C1 OAOVPBOWCVXFDD-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
Die Erfindung betrifft neue Imidazolderivate der allgemeinen Formel worin R1 C1-6-Alkyl oder Halogen bedeutet, R2 Wasserstoff, Hydroxy, Nitro, C1-6-Alkoxycarbonyl, Di(C1-6-alkyl)amino-C1-6-alkyl, Morpholino-C1-6-alkyl oder 4-Methylpiperazinyl-C1-6-alkyl bedeutet, R3 Wasserstoff oder C1-6-Alkyl bedeutet, R5 Amino oder C1-6-Alkyl bedeutet, R7 Wasserstoff oder C1-6-Alkyl bedeutet und R8 Wasserstoff oder Halogen bedeutet, und pharmazeutisch verwendbare Salze davon.The invention relates to new imidazole derivatives of the general formula wherein R 1 is C 1-6 alkyl or halogen, R 2 is hydrogen, hydroxy, nitro, C 1-6 alkoxycarbonyl, di (C 1-6 alkyl) amino-C 1-6 alkyl, morpholino-C 1 -6- alkyl or 4-methylpiperazinyl-C 1-6 alkyl means R 3 is hydrogen or C 1-6 alkyl, R 5 is amino or C 1-6 alkyl, R 7 is hydrogen or C 1-6 - Is alkyl and R 8 is hydrogen or halogen, and pharmaceutically acceptable salts thereof.
Der hierin verwendete Begriff "C1-6-Alkyl" bedeutet einzeln oder in Kombination eine geradkettige oder verzweigte Alkylgruppe mit 1–6 C-Atomen, wie Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, sec-Butyl, Isobutyl, tert-Butyl, n-Pentyl und n-Hexyl. Der Begriff "Halogen" oder "Halo" umfasst Fluor, Chlor, Brom und Jod.The term "C 1-6 alkyl" used herein means individually or in combination a straight-chain or branched alkyl group with 1-6 C atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl , tert-butyl, n-pentyl and n-hexyl. The term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine.
Methyl und Isopropyl sind bevorzugte C1-6-Alkylgruppen. Chlor ist ein bevorzugtes Halogenatom.Methyl and isopropyl are preferred C 1-6 alkyl groups. Chlorine is a preferred halogen atom.
Beispiele von bevorzugten Verbindungen
der Formel I sind:
4-[5-(4-Chlorphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl]-pyridin,
4-[5-(3-Methylphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl]pyridin,
3-Chlor-2-[4-(5-chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-phenylamin,
4-[5-(4-Chlorphenyl)-2-(2,6-diisopropylphenyl)imidazol-4-yl]pyridin,
3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzoesäuremethylester,
4-[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]morpholin,
[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]dimethylamin,
1-[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]-4-methylpiperazin,
4-[5-(4-Chlorphenyl)-2-(2,4,6-trimethyl-3-nitrophenyl)-imidazol-4-yl]pyridin,
3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylphenol
und
4-[5-(4-Fluorphenyl)-2-(2-brom-6-methylphenyl)-imidazol-4-yl]-pyridin.Examples of preferred compounds of the formula I are:
4- [5- (4-chlorophenyl) -2- (2,4,6-trimethylphenyl) imidazol-4-yl] -pyridine,
4- [5- (3-methylphenyl) -2- (2,4,6-trimethylphenyl) imidazol-4-yl] pyridine,
3-chloro-2- [4- (5-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -phenylamine,
4- [5- (4-chlorophenyl) -2- (2,6-diisopropylphenyl) imidazol-4-yl] pyridine,
3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzoesäuremethylester,
4- [3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzyl] morpholine,
[3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzyl] dimethylamine,
1- [3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzyl] -4-methylpiperazine,
4- [5- (4-chlorophenyl) -2- (2,4,6-trimethyl-3-nitrophenyl) -imidazol-4-yl] pyridine,
3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylphenol and
4- [5- (4-fluorophenyl) -2- (2-bromo-6-methylphenyl) -imidazol-4-yl] -pyridine.
Die Verbindungen der Formel I, die saure Funktionen enthalten, können pharmazeutisch verwendbare Salze mit Basen, wie Alkalimetallhydroxiden (beispielsweise Natriumhydroxid und Kaliumhydroxid), Erdalkalimetallhydroxiden (beispielsweise Calciumhydroxid und Magnesiumhydroxid) und Ammoniumhydroxid und dergleichen, bilden. Die Verbindungen der Formel I, die basische Funktionen enthalten, können pharmazeutisch verwendbare Salze mit Säuren bilden. Als solche Salze kommen nicht nur Salze mit anorganischen Säuren, wie Salzsäure oder Bromwasserstoffsäure, Schwefelsäure, Salpetersäure und Phosphorsäure, in Betracht, sondern auch Salze mit organischen Säuren, wie Essigsäure, Weinsäure, Bernsteinsäure, Fumarsäure, Maleinsäure, Äpfelsäure, Salicylsäure, Zitronensäure, Methansulfonsäure, p-Toluolsulfonsäure und so weiter.The compounds of formula I, the can contain acidic functions pharmaceutically acceptable salts with bases, such as alkali metal hydroxides (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide and magnesium hydroxide) and ammonium hydroxide and the like. The compounds of formula I, the basic Functions can contain Form pharmaceutically acceptable salts with acids. As such salts not only come with salts with inorganic acids, such as hydrochloric acid or hydrobromic, Sulfuric acid, nitric acid and phosphoric acid, into consideration, but also salts with organic acids, such as Acetic acid, Tartaric acid, Succinic acid, Fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and so on.
Die vorliegende Erfindung betrifft folglich Verbindungen der Formel I und deren pharmazeutisch verwendbare Salze an sich und deren Verwendung als therapeutische Wirkstoffe, ein Verfahren zur Herstellung dieser Verbindungen und der Salze davon, Arzneimittel, die diese Verbindungen oder Salze enthalten und die Herstellung von diesen Arzneimitteln und die Verwendung der Verbindungen und deren Salze für die Bekämpfung von Krankheiten, insbesondere hyperproliferative Störungen, wie Arteriosklerose, Psoriasis und Tumore, und für die Behandlung von Alopezie oder für die Herstellung eines Arzneimittels für die Behandlung oder Verhinderung solcher Störungen.The present invention relates to consequently compounds of formula I and their pharmaceutically usable Salts per se and their use as therapeutic agents, a process for the preparation of these compounds and the salts of which, drugs containing these compounds or salts and the manufacture of these drugs and their use of compounds and their salts for combating diseases, in particular hyperproliferative disorders, such as arteriosclerosis, psoriasis and tumors, and for the treatment of alopecia or for the manufacture of a medicament for treatment or prevention such disorders.
Die pharmakologische Wirkung der erfindungsgemäßen Verbindungen kann auf der Grundlage ihrer Wirkung auf Proteinkinaseinhibitoren und Inhibitoren von HaCaT-Zellproliferation bestimmt werden. Insbesondere sind die erfindungsgemäßen Verbindungen selektive Inhibitoren von epidermalem Wachstumsfaktor (EGF-R)-Tyrosinkinase.The pharmacological effects of compounds of the invention can be based on their action on protein kinase inhibitors and inhibitors of HaCaT cell proliferation can be determined. In particular are the compounds of the invention selective inhibitors of epidermal growth factor (EGF-R) tyrosine kinase.
EGF-R spielt eine Rolle bei der Entwicklung und Metastatisierung von bestimmten humanen, malignen Erkrankungen, wie Brustkrebs, Leberkrebs und Prostatakrebs.EGF-R plays a role in the development and metastasis of certain human, malignant diseases, like breast cancer, liver cancer and prostate cancer.
Für alle bekannten Funktionen und Wirkungen von EGF-R ist eine Tyrosinkinasewirksamkeit ein bestimmender Faktor. Die Inhibierung dieser enzymatischen Aktivität durch die Verbindung der Formel I kann deshalb als ein Maß für die Wirksamkeit bei der therapeutischen Behandlung von EGF-R-vermittelten hyperproliferativen Erkrankungen, wie bestimmten Formen von Krebs uns Psoriasis, angesehen werden.For all known functions and effects of EGF-R is tyrosine kinase activity a determining factor. The inhibition of this enzymatic activity by the compound of formula I can therefore be used as a measure of effectiveness in the therapeutic treatment of EGF-R-mediated hyperproliferative diseases, how certain forms of cancer and psoriasis are viewed.
Im Gegensatz zu der stimulierenden Rolle des EGF-Rezeptors bei der Keratinocytenproliferation zeigen in vitro- und in vivo-Studien, dass die Aktivierung dieses Rezeptors ein negativer Regulator für Haarfollikelaktivität ist. Somit inhibiert die Injektion von EGF Haarwuchs bei neugeborenen Mäusen (Moore et al., J. Endocrinol 88, 293 [1981]) und Schafen (Chapman & Hardy von J. Biol. Sci. 41, 261 [1988]) und die Behandlung von gezüchteten menschlichen Haarfollikeln mit EGF induziert einen catagenähnlichen Zustand (Philpott et al., J. Cell Sci. 97, 463 [1990]) unter Inhibierung der Haarfaserproduktion. Diese Erkenntnisse lassen vermuten, dass die Inhibierung von EGF-R Tyrosinkinase Haarwuchs stimuliert und die Dauer der Anagenphase des Haarzyklus in vivo verlängert.In contrast to the stimulating Role of the EGF receptor in keratinocyte proliferation show in vitro and in vivo studies, that the activation of this receptor is a negative regulator for hair follicle activity. Consequently inhibits the injection of EGF hair growth in newborn mice (Moore et al., J. Endocrinol 88, 293 [1981]) and sheep (Chapman & Hardy by J. Biol. Sci. 41, 261 [1988]) and the treatment of bred human hair follicles with EGF induce a catagen-like Condition (Philpott et al., J. Cell Sci. 97, 463 [1990]) with inhibition of hair fiber production. These findings suggest that inhibits EGF-R tyrosine kinase hair growth and extends the duration of the anagen phase of the hair cycle in vivo.
Relevanter Stand der Technik ist:
- (1) DE-A-22 21 5465
- (2) US-A-37 72 441
- (3) WO-A-93/14081
- (4) Proc. Natl. Acad. Sci. 87, 782 (1990)
- (5) Int. J. Biochem. 26, 1203 (1994)
- (6) EP-A-0 384 349
- (7) WO-A-94/03427
- (8) WO-A-95/03297
- (9) WO-A-95/07922
- (10) Curr. Opin. Biotechnol. 6, 657 (1995)
- (11) Ann. N. Y. Acad. Sci. 696, 149 (1993)
- (12) WO-A-93/14082
- (1) DE-A-22 21 5465
- (2) US-A-37 72 441
- (3) WO-A-93/14081
- (4) Proc. Natl. Acad. Sci. 87, 782 (1990)
- (5) Int. J. Biochem. 26, 1203 (1994)
- (6) EP-A-0 384 349
- (7) WO-A-94/03427
- (8) WO-A-95/03297
- (9) WO-A-95/07922
- (10) curr. Opin. Biotechnol. 6, 657 (1995)
- (11) Ann. NY Acad. Sci. 696, 149 (1993)
- (12) WO-A-93/14082
Besonders hervorzuheben sind die trisubstituierten Imidazole von WO 93/14081, die im Vergleich zu den erfindungsgemäßen trisubstituierten Triazolen andere Substitutionsmuster an dem 2-Phenyl aufweisen; die erfindungsgemäßen an dem 2-Phenyl sind mindestens 2,6-disubstituiert, ein Merkmal, das in den Imidazolen von WO 93/14081 nicht vorliegt.They are particularly noteworthy trisubstituted imidazoles from WO 93/14081, which compared to the trisubstituted according to the invention Triazoles have other substitution patterns on the 2-phenyl; the according to the invention 2-phenyl are at least 2,6-disubstituted, a feature that is described in the imidazoles from WO 93/14081 is not present.
Die biologische Wirkung der erfindungsgemäßen Verbindungen wurde in verschiedenen Testmodellen, die nachstehend beschrieben werden, getestet.The biological effect of the compounds according to the invention has been used in various test models, described below will be tested.
Tyrosinproteinkinasentyrosine protein kinases
Inhibierung von EGF-Rezeptor-TyrosinkinaseInhibition of EGF receptor tyrosine kinase
Die Aktivität der EGF-Rezeptor-Tyrosinkinase
wird durch Messen der Übertragung
von 32P-markiertem Phosphat aus 32P-γ-ATP
(10 μM)
an das Substrat RR-scr-Peptid* (0,75 mM) bestimmt. Eine Membranfraktion aus
humanen A431-Zellen wird als das Enzym verwendet. Es wird gemäß Thom et
al., Biochem. J. 168, 187 (1977) isoliert und bei –75°C gelagert.
(4–6 mg
Protein/ml). Die Verbindungen werden in 10%igem DMSO bei einer Konzentration
von 0,001–100 μM getestet.
Die Inkubation wird bei 30°C
für einen
Zeitraum von 30 Minuten in Trispuffer (25 mM, pH 7,4) ausgeführt, welcher
Magnesiumacetat (30 mM), Natriumvanadat (0,5 mM), 0,5% BSA und 0,05%
Triton X-100 enthält.
Die Membranen werden mit 2 μM
EGF bei 4°C
für 90
Minuten vorinkubiert. Der Test wird durch Zugeben des Enzyms (2 μg Membranprotein)
begonnen und durch Zugeben von eiskaltem KHP2O4 (1 M, pH 3,0) beendet. Nach Zentrifugierung
wird das markierte Peptid von überschüssigem ATP
in dem Überstand
durch Umkehrphasen-HPLC getrennt. Die Peptidfraktion wird gesammelt
und die Radioaktivität
wird in einem Standard-β-Zähler oder online mit einem
Radiometer (Berthold) gemessen. Die Inhibitorwirksamkeit der Testverbindung
wird als die mikromolare Konzentration ausgedrückt, die für 50% Inhibierung erforderlich
ist (IC50 [μM]).
*RR-src-Peptid=[Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly]The activity of the EGF receptor tyrosine kinase is determined by measuring the transfer of 32 P-labeled phosphate from 32 P-γ-ATP (10 μM) to the substrate RR-scr peptide * (0.75 mM). A membrane fraction from human A431 cells is used as the enzyme. It is according to Thom et al., Biochem. J. 168, 187 (1977) isolated and stored at -75 ° C. (4-6 mg protein / ml). The compounds are tested in 10% DMSO at a concentration of 0.001-100 μM. The incubation is carried out at 30 ° C for a period of 30 minutes in Tris buffer (25 mM, pH 7.4), which contains magnesium acetate (30 mM), sodium vanadate (0.5 mM), 0.5% BSA and 0.05 % Triton X-100 contains. The membranes are preincubated with 2 μM EGF at 4 ° C for 90 minutes. The test is started by adding the enzyme (2 μg membrane protein) and ended by adding ice-cold KHP 2 O 4 (1 M, pH 3.0). After centrifugation, the labeled peptide is separated from excess ATP in the supernatant by reverse phase HPLC. The peptide fraction is collected and the radioactivity is measured in a standard β counter or online with a radiometer (Berthold). The inhibitory activity of the test compound is expressed as the micromolar concentration required for 50% inhibition (IC50 [μM]).
* RR-src peptide = [Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly]
Inhibierung von p56Ick-TyrosinkinaseInhibition of p56 Ick tyrosine kinase
Die Wirksamkeit von p56Ick-Tyrosinkinase wird durch Messen der Übertragung von 32P-markiertem Phosphat aus 32P-γ ATP (10 μM) zu dem Substrat RR-src Peptid* (0,75 mM) bestimmt. Humanes rekombinantes p56Ick (exprimiert in E. coli) wird als das Enzym verwendet. Es wird aus der löslichen Fraktion mit Hilfe eines monoklonalen Antikörpers gereinigt und bei –75°C gelagert. Die Verbindungen werden in 10%igem DMSO in einer Konzentration von 0,001–100 μM getestet. Die Inkubation wird bei 30°C für einen Zeitraum von 30 Minuten in HEPES-Puffer (50 mM, pH 6,9) ausgeführt, welche Manganchlorid (11 mM) und 0,5% BSA enthält. Der Test wird durch Zugeben des Enzyms gestartet und durch Zugeben von eiskaltem KHP2O4 (1 M, pH 3,0) beendet. Nach Zentrifigierung wird das radiomarkierte Peptid von überschüssigem ATP in dem Überstand durch Umkehrphasen-HPLC abgetrennt. Die Peptidfraktion wird gesammelt und die Radioaktivität wird in einem Standard-β-Zähler oder online mit einem Radiometer (Berthold) bestimmt. Die Inhibitorwirksamkeit der Testverbindung wird als die mikromolare Konzentration ausgedrückt, die für 50% Inhibierung erforderlich ist. (IC50 [μM]).The effectiveness of p56 Ick tyrosine kinase is determined by measuring the transfer of 32 P-labeled phosphate from 32 P-γ ATP (10 μM) to the substrate RR-src peptide * (0.75 mM). Human recombinant p56 Ick (expressed in E. coli) is used as the enzyme. It is purified from the soluble fraction using a monoclonal antibody and stored at -75 ° C. The compounds are tested in 10% DMSO in a concentration of 0.001-100 μM. The incubation is carried out at 30 ° C. for a period of 30 minutes in HEPES buffer (50 mM, pH 6.9) which contains manganese chloride (11 mM) and 0.5% BSA. The test is started by adding the enzyme and ended by adding ice-cold KHP 2 O 4 (1 M, pH 3.0). After centrifugation, the radiolabeled peptide is separated from excess ATP in the supernatant by reverse phase HPLC. The peptide fraction is collected and the radioactivity is determined in a standard β counter or online with a radiometer (Berthold). The inhibitor effectiveness of the test compound is expressed as the micromolar concentration required for 50% inhibition. (IC 50 [µM]).
Serin/Threonin-ProteinkinasenSerine / threonine protein kinases
Inhibierung von cAMP-abhängiger Proteinkinase (PKA)Inhibition of cAMP-dependent protein kinase (PKA)
Die Wirksamkeit von PKA wird durch Messen der Übertragung von 32P-markiertem Phosphat von 32P-γ-ATP (10 μM) zu dem Substrat Histon H1 (333 μg/ml) unter Verwendung von teilweise gereinigtem PKA von Hausschweinhirn (DEAE-Chromatografie, gemäß U. Kikkawa et al., Methods Enzymol. 99, 288, 1983) gemessen. PKA wird durch 2 μM cAMP in Tris-HCl-Puffer (20 mM, pH 7,4) aktiviert. Die Verbindungen werden in DMSO/Puffer bei einer Konzentration von 0,001–100 μM getestet. Der Test wird durch Zugeben des Enzyms begonnen, nimmt 2 Minuten bei 32°C in Anspruch und wird durch Zugeben von 20%iger Trichloressigsäure (enthaltend 1% SDS und 1% Natriumpyrophosphat) beendet. Das ausgefällte Protein, das das radiomarkierte Histon erhält, wird von überschüssigem ATP durch Filtration durch ein Nitrozellulosemembranfilter getrennt. Die Radioaktivität des Filters wird in einem Scintillationszähler bestimmt. Die Inhibitorwirkung der Testverbindungen wird als die mikromolare Konzentration ausgedrückt, die für 50% Inhibierung erforderlich ist (IC50 [μM]).The effectiveness of PKA is assessed by measuring the transfer of 32 P-labeled phosphate from 32 P-γ-ATP (10 μM) to the substrate histone H1 (333 μg / ml) using partially purified porcine brain PKA (DEAE chromatography, according to U. Kikkawa et al., Methods Enzymol. 99, 288, 1983). PKA is activated by 2 μM cAMP in Tris-HCl buffer (20 mM, pH 7.4). The compounds are tested in DMSO / buffer at a concentration of 0.001-100 μM. The test is started by adding the enzyme, takes 2 minutes at 32 ° C and is ended by adding 20% trichloroacetic acid (containing 1% SDS and 1% sodium pyrophosphate). The precipitated protein that receives the radiolabeled histone is separated from excess ATP by filtration through a nitrocellulose membrane filter. The radioactivity of the filter is determined in a scintillation counter. The inhibitory activity of the test compounds is expressed as the micromolar concentration required for 50% inhibition (IC 50 [μM]).
Inhibierung von Proteinkinase C (PKC)Inhibition of protein kinase C (PKC)
Die Wirksamkeit von PKC wird durch Messen der Übertragung von 32P-markiertem Phosphat von 32P-β-ATP (10 μM) zu dem Substrat Histon H1 (200 μg/ml) unter Verwendung von teilweise gereinigtem PKC von Hausschweinhirn (DEAE-Chromato grafie gemäß U. Kikkawa et al., Methods Enzymol. 99, 288, 1983) gemessen. PKC wird durch Phospholipidvesikel, hergestellt durch Beschallen eines Gemisches von 0,05 ml Phosphatidylserin (10 mg/ml) und 0,005 ml Diolein (10 mg/ml) in 5 ml Tris-HCl-Puffer (20 mM, pH 7,4), aktiviert. Die Verbindungen werden in DMSO/Puffer bei einer Konzentration von 0,001–100 μM getestet. Der Test wird durch Zugeben des Enzyms begonnen, nimmt 2 Minuten bei 32°C in Anspruch und wird durch Zugeben von 20%iger Trichloressigsäure (enthaltend 1% SDS und 1% Natriumpyrophosphat) beendet. Das ausgefällte Protein mit dem markierten Histon wird von überschüssigem ATP durch Filtration über ein Nitrozellulosemembranfilter getrennt. Die Radioaktivität auf dem Filter wird in einem Scintillationzähler gemessen. Die Inhibitorwirkung der Testverbindung wird als die mikromolare Konzentration ausgedrückt, die für 50% Inhibierung erforderlich ist (IC50 [μM]).The effectiveness of PKC is assessed by measuring the transfer of 32 P-labeled phosphate from 32 P-β-ATP (10 μM) to the histone H1 substrate (200 μg / ml) using partially purified porcine brain PKC (DEAE chromatography) according to U. Kikkawa et al., Methods Enzymol. 99, 288, 1983). PKC is produced by phospholipid vesicles, sonicated by a mixture of 0.05 ml phosphatidylserine (10 mg / ml) and 0.005 ml diolein (10 mg / ml) in 5 ml Tris-HCl buffer (20 mM, pH 7.4), activated. The compounds are tested in DMSO / buffer at a concentration of 0.001-100 μM. The test is started by adding the enzyme, takes 2 minutes at 32 ° C and is ended by adding 20% trichloroacetic acid (containing 1% SDS and 1% sodium pyrophosphate). The precipitated protein with the labeled histone is separated from excess ATP by filtration through a nitrocellulose membrane filter. The radioactivity on the filter is measured in a scintillation counter. The inhibitory activity of the test compound is expressed as the micromolar concentration required for 50% inhibition (IC 50 [μM]).
Inhibierung von HaCaT-ZellproliferationInhibition of HaCaT cell proliferation
HaCaT ist die spontan immortalisierte Human-Keratinoyctenzelllinie (Boukamp et al. 1988), die viele Male als ein Modellsystem für hyperproliferative Keratinoycten verwendet wurde. Der Einbau von [3H]-Thymidin wurde angewendet, um das Wachstum der Zellen in der S-Phase des Zellzyklus zu quantifizieren. Die Zellen wurden mit einem 3 : 1 Gemisch von DMEM/F12 Medium gezüchtet, das mit 5%igem FCS, EGF (10 μg/l), Hydrocortison (400 μg/l), Choleratoxin (8,5 μg/l), Insulin (5 μg/l), L-Glutamin (2 mM) und Penicillin/Streptomycin ergänzt wurde. 200 μl Medium wurden auf Mikrotiterplatten angeordnet, sodass jede Probe 5000 Zellen enthielt. Die Testverbindungen wurden in seriellen Verdünnungen im Bereich von 1 × 10–8 M bis 1 × 10–5 M am Beginn der Züchtung zugegeben. Die Zellen wurden bei 37°C für 48 Stunden inkubiert. Für die letzten 6 Stunden wurde [3H]-Thymidin zugegeben (1 mCi/Probe). Nach Verdau der Zellen mit Trypsin wurde die Menge an eingebauter Radioaktivität mit einem Flüssigszintillationzähler quantifiziert.HaCaT is the spontaneously immortalized human keratinocyte cell line (Boukamp et al. 1988), which has been used many times as a model system for hyperproliferative keratinocytes. Incorporation of [ 3 H] thymidine was used to quantify cell growth in the S phase of the cell cycle. The cells were grown with a 3: 1 mixture of DMEM / F12 medium containing 5% FCS, EGF (10 ug / l), hydrocortisone (400 ug / l), cholera toxin (8.5 ug / l), insulin (5 μg / l), L-glutamine (2 mM) and penicillin / streptomycin was added. 200 ul medium was placed on microtiter plates so that each sample contained 5000 cells. The test compounds were added in serial dilutions ranging from 1 x 10 -8 M to 1 x 10 -5 M at the start of cultivation. The cells were incubated at 37 ° C for 48 hours. [ 3 H] -Thymidine was added for the last 6 hours (1 mCi / sample). After digesting the cells with trypsin, the amount of radioactivity incorporated was quantified using a liquid scintillation counter.
Die Inhibierung von ausgewählten Proteinkinasen in vitro und die Inhibierung von Zellproliferation in HaCaT-Zellen durch diese Verbindungen werden in der nachstehenden Tabelle angeführt.The inhibition of selected protein kinases in vitro and the inhibition of cell proliferation in HaCaT cells by this Compounds are listed in the table below.
Stimulation von Zellproliferation in gezüchteten MaushaarfollikelnStimulation of cell proliferation in bred Maushaarfollikeln
Maushaarfollikel werden isoliert und gemäß dem Verfahren, beschrieben von Buhl et al., J. Invest. Dermatol. 92, 315 (1989) gezüchtet. Die Barthaarteile (Whisker) werden aus 4 Tage alten CD-1-Mäusen entfernt, und die Haarfollikel werden vorsichtig von dem umgebenden Gewebe unter dem Mikroskop entfernt. Haarfollikel werden in M199-Medium gezüchtet, das 20% FBS enthält, und die Zellproliferation wird aus dem Einbau von (3H]-Thymidin in DNA bestimmt. Die Testverbindungen werden in DMSO gelöst und in seriellen Verdünnungen im Bereich von 1 × 10–8 bis 1 × 10–6 M am Beginn der Züchtung zugesetzt. Nach 1 Tag werden 5 μCi/ml [3H]-Thymidin zu dem Kul turmedium gegeben und die Follikel werden für weitere 3 Tage inkubiert. Die Haarfollikel werden dann mit Phosphat gepufferter Salzlösung gewaschen, um die nicht eingebaute Radioaktivität zu entfernen und die DNA wird durch Inkubation mit Alkali über Nacht solubilisiert. Die durch die follikuläre DNA eingebaute Radioaktivität wird dann unter Verwendung eines Flüssigszintillationszählers gemessen.Mouse hair follicles are isolated and according to the method described by Buhl et al., J. Invest. Dermatol. 92, 315 (1989). The whiskers are removed from CD-1 mice, 4 days old, and the hair follicles are carefully removed from the surrounding tissue under the microscope. Hair follicles are grown in M199 medium containing 20% FBS and cell proliferation is determined from the incorporation of ( 3 H] -thymidine in DNA. The test compounds are dissolved in DMSO and in serial dilutions in the range of 1 x 10 -8 to 1 x 10 -6 M at the start of cultivation, after 1 day 5 µCi / ml [ 3 H] -thymidine is added to the culture medium and the follicles are incubated for a further 3 days, the hair follicles are then buffered with phosphate buffered saline washed to remove the unincorporated radioactivity, and the DNA is solubilized by overnight incubation with alkali, and the radioactivity incorporated by the follicular DNA is then measured using a liquid scintillation counter.
Die Inkubation von Maushaarfollikeln mit der Verbindung von Beispiel 1 ergibt eine Stimulierung der Zellproliferation mit einem maximalen DNA-Synthesewert von 211 ± 17% (verglichen mit Kontrollen) bei einer Konzentration von 0,3 μM. Die Konzentration, die sich in einem halben Maximum Stimulierung der DNA-Synthese ergibt (EC50 Wert), war 0,1 μM. Die Wirksamkeit der Verbindung von Beispiel 1 in diesem Kultursystem überstieg jene von bekannten hypotrichotischen Mitteln. Beispielsweise stimuliert Minoxidil die Haarfollikel-DNA-Synthese auf 160 ± 15% (verglichen mit Kontrollen) und hat einen EC50-Wert von 200 μM.Incubation of mouse hair follicles with the compound of Example 1 gives stimulation of cell proliferation with a maximum DNA synthesis value of 211 ± 17% (compared to controls) at a concentration of 0.3 μM. The concentration resulting in half a maximum stimulation of DNA synthesis (EC50 value) was 0.1 μM. The potency of the compound of Example 1 in this culture system exceeded that of known hypotrichotic agents. For example, Minoxidil stimulates hair follicle DNA synthesis to 160 ± 15% (compared to controls) and has an EC 50 value of 200 μM.
Erfindungsgemäß können die Verbindungen der Formel
I und deren pharmazeutisch verwendbare Salze durch Umsetzen eines
Diketons der allgemeinen Formel worin R7 und
R8 die vorstehend angegebene Bedeutung aufweisen,
mit
einem Aldehyd der allgemeinen Formel
worin R1,
R2, R3 und R5 die vorstehend angegebene Bedeutung aufweisen
und worin eine Hydroxygruppe in einer Verbindung der Formel III
in geschützter
Form vorliegen kann, in Gegenwart von Ammoniak, Abspaltung einer
Hydroxyschutzgruppe, die vorliegen kann, und, falls erwünscht, funktionelles
Modifizieren von reaktiven Gruppen, die in einer erhaltenen Verbindung
der Formel I vorliegen, und, falls erwünscht, Umwandeln einer Verbindung
der Formel I in ein pharmazeutisch verwendbares Salz, hergestellt
werden.According to the invention, the compounds of the formula I and their pharmaceutically acceptable salts can be reacted by reacting a diketone of the general formula wherein R 7 and R 8 have the meaning given above,
with an aldehyde of the general formula wherein R 1 , R 2 , R 3 and R 5 have the meaning given above and wherein a hydroxy group in a compound of formula III may be in protected form, in the presence of ammonia, cleavage of a hydroxy protecting group which may be present, and if desired , functional modifying reactive groups present in an obtained compound of formula I and, if desired, converting a compound of formula I into a pharmaceutically acceptable salt.
Die Reaktion eines Diketons der Formel II mit einem Aldehyd der Formel III und mit Ammoniak kann in einer an sich bekannten weise ausgeführt werden. Beispielsweise kann ein Diketon der Formel II mit einem Aldehyd der Formel III und mit Ammoniumacetat (ein Reagenz, das Ammoniak freisetzt) in einer organischen Säure, wie Essigsäure bei einer erhöhten Temperatur, beispielsweise etwa 50 bis etwa 100°C umgesetzt werden.The reaction of a diketone of the formula II with an aldehyde of formula III and with ammonia can in one performed in a manner known per se become. For example, a diketone of formula II with an aldehyde of formula III and with ammonium acetate (a reagent that ammonia releases) in an organic acid, such as acetic acid an elevated Temperature, for example about 50 to about 100 ° C are implemented.
Eine Hydroxygruppe in einer Verbindung der Formel III kann in der Reaktion gemäß der Erfindung in geschützter Form, beispielsweise als ein Benzylether vorliegen, der aus dem Reaktionsprodukt in an sich bekannter Weise, im Fall von Benzylether beispielsweise durch katalytische Hydrierung, entfernt werden kann.A hydroxy group in a compound of the formula III can in the reaction according to the invention in protected form, for example, be present as a benzyl ether resulting from the reaction product in a manner known per se, for example in the case of benzyl ether can be removed by catalytic hydrogenation.
Die Diketone der Formel II und Aldehyde der Formel III sind bekannt oder können in an sich bekannter Weise, wie in den Beispielen beschrieben oder in Analogie dazu, hergestellt werden.The diketones of formula II and aldehydes of the formula III are known or can be carried out in a manner known per se, as described in the examples or in analogy become.
Funktionelle Modifizierung von reaktiven Gruppen kann beispielsweise die Verseifung von Estergruppen, die Reduktion von Nitrogruppen zu Aminogruppen und die Alkylierung von Aminogruppen umfassen. Diese funktionellen Modifizierungen können in an sich bekannter Weise, beispielsweise wie in den Beispielen beschrieben oder in Analogie dazu, ausgeführt werden.Functional modification of reactive Groups can, for example, the saponification of ester groups Reduction of nitro groups to amino groups and the alkylation of Include amino groups. These functional modifications can be found in in a manner known per se, for example as described in the examples or in analogy become.
Saure Verbindungen der Formel I können durch Behandlung mit Basen zu pharmazeutisch verwendbaren Salzen umgewandelt werden und basische Verbindungen der Formel I können durch Behandlung mit Säuren zu pharmazeutisch verwendbaren Salzen umgewandelt werden. Solche Reaktionen können in an sich bekannter Weise ausgeführt werden.Acidic compounds of formula I can by Treatment with bases converted to pharmaceutically acceptable salts and basic compounds of formula I can by treatment with acids pharmaceutically acceptable salts can be converted. Such reactions can be carried out in a manner known per se.
Die Verbindungen der Formel I und deren Salze können als Arzneimittel, beispielsweise in Form von pharmazeutischen Zubereitungen, verwendet werden.The compounds of formula I and whose salts can as medicinal products, for example in the form of pharmaceutical preparations, be used.
Die Arzneimittel können enteral, parenteral oder örtlich verabreicht werden. Arzneimittel in Form von Tabletten, Kapseln, Dragees, Sirupen, Suspensionen, Lösungen und Suppositorien sind beispielsweise für die enterale Verabreichung geeignet. Arzneimittel in Form von Infusions- oder Injektionslösungen sind für die parenterale Verabreichung geeignet.The drugs can be enteral, parenterally or locally be administered. Medicines in the form of tablets, capsules, Dragees, syrups, suspensions, solutions and suppositories are for example for enteral administration is suitable. Medicines in the form of infusion or injection solutions are for parenteral administration is suitable.
Die Dosierungen, in denen die Zubereitungen verabreicht werden, können gemäß der Verwendungsart und dem Verwendungsweg sowie gemäß den Erfordernissen des Patienten variieren.The dosages in which the preparations can be administered according to the type of use and the route of use and according to requirements of the patient vary.
Bei der oralen Verabreichung der erfindungsgemäßen Verbindungen kommen im Fall von Erwachsenen Dosierungen von etwa 0,1–100 mg/kg, vorzugsweise 0,5–50 mg/kg, pro Tag in Betracht.When administered orally compounds of the invention in the case of adults, dosages of around 0.1-100 mg / kg preferably 0.5-50 mg / kg, per day.
Die Zubereitungen können in einer oder mehreren Dosen verabreicht werden. Kapseln, die etwa 5–500 mg des Wirkbestandteils enthalten, umfassen eine bevorzugte Verabreichungsform.The preparations can be made in one or more doses. Capsules containing approximately 5–500 mg of the active ingredient comprise a preferred administration form.
Die Zubereitungen können inerte oder pharmakodynamisch aktive Zusätze enthalten. Tabletten oder Granulate können beispielsweise eine Reihe von Bindemitteln, Füllstoffen, Trägern oder Verdünnungsmitteln enthalten. Flüssige Zubereitungen können beispielsweise in Form einer Mischlösung mit sterilem Wasser vorliegen. Kapseln können einen Füllstoff oder ein Verdickungsmittel zusätzlich zu dem Wirkbestandteil enthalten. Weiterhin können geschmacksverbessernde Zusätze, sowie Substanzen, die gewöhnlich als Konservierungsmittel verwendet werden, Stabilisatoren, Feuchtigkeitsmittel und Emulgatoren, sowie Salze zum Variieren des osmotischen Drucks, Puffer und andere Zusätze vorliegen.The preparations can be inert or contain pharmacodynamically active additives. Tablets or granules can for example a number of binders, fillers, carriers or Contain diluents. liquid Preparations can for example in the form of a mixed solution with sterile water. Capsules can a filler or an additional thickener included in the active ingredient. Furthermore, taste-improving Additives, as well Substances common used as preservatives, stabilizers, moisturizers and emulsifiers, and salts for varying the osmotic pressure, Buffers and other additives available.
Die vorstehend erwähnten Träger und Verdünnungsmittel können organische oder anorganische Substanzen, beispielsweise Wasser, Gelatine, Laktose, Stärke, Magnesiumstearat, Talkum, Gummi arabicum, Polyalkylenglycole und dergleichen, umfassen. Es ist erforderlich, dass alle in der Herstellung der Zubereitung verwendeten Hilfsmittel nicht toxisch sind.The aforementioned carriers and thinner can organic or inorganic substances, for example water, Gelatin, lactose, starch, Magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. It is required that everyone in the making auxiliaries used in the preparation are not toxic.
Zur örtlichen Anwendung werden die Wirkbestandteile geeigneterweise in Form von Salben, Tinkturen, Cremes, Lösungen, Lotionen, Sprays, Suspensionen, Gelen und dergleichen angewendet. Salben und Cremes sowie Lösungen sind bevorzugt. Diese Zubereitungen, die zur örtlichen Auftragung angepasst sind, können durch Vermischen der Verfahrensprodukte als Wirkbestandteile mit nichttoxischen, inerten festen oder flüssigen Trägern, die zur örtlichen Behandlung geeignet sind und die üblicherweise in solchen Zubereitungen vorliegen, hergestellt werden.For local application, the Active ingredients suitably in the form of ointments, tinctures, Creams, solutions, Lotions, sprays, suspensions, gels and the like applied. Ointments and creams as well as solutions are preferred. These preparations are adapted for local application are, can by mixing the process products with active ingredients non-toxic, inert solid or liquid carriers used for local Are suitable for treatment and are usually present in such preparations, getting produced.
Zur örtlichen Auftragung gibt es zweckmäßigerweise geeigneterweise etwa 0,1–10%, vorzugsweise 0,3–2% Lösungen, sowie etwa 0,1–10%, vorzugsweise etwa 0,3–2%, Salben und Cremes.For topical application there is suitably about 0.1-10%, preferably 0.3-2% solutions, as well as about 0.1-10%, preferably about 0.3-2%, ointments and creams.
Falls erwünscht, kann ein Antioxidationsmittel, beispielsweise Tocopherol, N-Methyl-γ-tocopheramin, sowie t-Butylhydroxyanisol oder t-Butyl-hydroxytoluol, mit den Zubereitungen angemischt werden.If desired, an antioxidant, for example tocopherol, N-methyl-γ-tocopheramine, and t-butylhydroxyanisole or t-butyl-hydroxytoluene, are mixed with the preparations.
Die nachstehenden Beispiele erläutern die Erfindung genauer.The following examples illustrate the Invention more precisely.
Beispiel 1example 1
Ein Gemisch von 12,3 g 1-(4-Chlorphenyl)-2-pyridin-4-yl-ethandion und 7,4 g 2,4,6-Trimethylbenzaldehyd in 125 ml Essigsäure, die 40 g Ammoniumacetat enthält, wurde 2 Stunden bei 100°C gerührt, dann auf Raumtemperatur abkühlen lassen. Das Gemisch wurde in ein Gemisch von 300 ml Eiswasser und 200 ml konzentrierter Ammoniaklösung gegossen und das Gemisch wurde dreimal mit Essigsäureethylester extrahiert. Nach Trocknen über wasserfreiem Magnesiumsulfat wurde das Lösungsmittel verdampft. Der Rückstand wurde durch Chromatografie an Kieselgel mit Dichlormethan/Methanol (9 : 1) gereinigt und aus Essigsäureethylester kristallisiert, unter Gewinnung von 6,7 g 4-[5-(4-Chlorphenyl)-2-(2,4,6-trimethyphenyl)imidazol-4-yl]pyridin, Fp. 275°C.A mixture of 12.3 g of 1- (4-chlorophenyl) -2-pyridin-4-yl-ethanedione and 7.4 g of 2,4,6-trimethylbenzaldehyde in 125 ml of acetic acid, the Contains 40 g ammonium acetate, was 2 hours at 100 ° C touched, then cool to room temperature to let. The mixture was poured into a mixture of 300 ml of ice water and 200 ml concentrated ammonia solution poured and the mixture was thrice with ethyl acetate extracted. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The Residue was by chromatography on silica gel with dichloromethane / methanol (9: 1) purified and made from ethyl acetate crystallized, to obtain 6.7 g of 4- [5- (4-chlorophenyl) -2- (2,4,6-trimethyphenyl) imidazol-4-yl] pyridine, mp. 275 ° C.
Beispiele 2–17Examples 2-17
Die nachstehenden Verbindungen wurden in Analogie zu Beispiel 1 hergestellt:
- 2. 4-[5-(4-Fluorphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl]pyridin, Fp. 252–254°C (Diethylether),
- 3. 4-[5-(4-Chlorphenyl)-2-(2,6-dimethylphenyl)imidazol-4-yl]-pyridin, Fp. 290–292°C (Essigsäureethylester/Hexan),
- 4. 4-[5-(3-Methylphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl]pyridin, Fp. 251–253°C (Diethylether),
- 5. 4-[5-(4-Chlorphenyl)-2-(2-chlor-6-methylphenyl)-imidazol-4-yl]pyridin, Fp. > 260°C (Aceton),
- 6. 4-(5-(4-Chlorphenyl)-2-(2-brom-6-methylphenyl)-imidazol-4-yl]pyridin, Fp. > 260°C (Aceton/Hexan),
- 7. 4-[5-(4-Chlorphenyl)-2-(2,6-diisopropylphenyl)imidazol-4-yl]pyridin, Fp. > 260°C (Aceton/Hexan),
- 8. 4-[5-(4-Fluorphenyl)-2-(2-brom-6-methylphenyl)-imidazol-4-yl]pyridin, Fp. > 260°C (Dichlormethan),
- 9. 3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzoesäuremethylester, Fp. 228°C (Essigsäureethylester/Isopropylether),
- 10. 4-[5-(4-Chlorphenyl)-2-(2,6-dimethyl-3-nitrophenyl)-imidazol-4-yl)pyridin, Fp. 295–298°C (Essigsäureethylester/Hexan),
- 11. 4-[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6,-trimethylbenzyl]morpholin, Fp. 239–240°C (Essigsäureethylester),
- 12. [3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]dimethylamin, Fp. 222°C (Acetonitril),
- 13. 1-[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]-4-methylpiperazin, Fp. 280°C (Essigsäureethylester),
- 14. 3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4-dimethylphenol, Fp. > 300°C (Ethanol),
- 15. 4-[5-(4-Chlorphenyl)-2-(2,4,6-trimethyl-3-nitrophenyl)imidazol-4-yl]pyridin, Fp. 295–299°C (Methanol/Essigsäuresäureethylester),
- 16. 3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylphenol, Fp. > 300°C (Ethanol),
- 17. (2RS,6RS)- und (2R,6S)-4-[3-[5-(4-Chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]-2,4,6-trimethylbenzyl]-2,6-dimethylmorpholin, Fp. 163–170°C (Essigsäureethylester).
- 2. 4- [5- (4-fluorophenyl) -2- (2,4,6-trimethylphenyl) imidazol-4-yl] pyridine, mp. 252-254 ° C (diethyl ether),
- 3. 4- [5- (4-chlorophenyl) -2- (2,6-dimethylphenyl) imidazol-4-yl] pyridine, mp. 290-229 ° C (ethyl acetate / hexane),
- 4. 4- [5- (3-methylphenyl) -2- (2,4,6-trimethylphenyl) imidazol-4-yl] pyridine, mp. 251-253 ° C (diethyl ether),
- 5. 4- [5- (4-chlorophenyl) -2- (2-chloro-6-methylphenyl) imidazol-4-yl] pyridine, mp> 260 ° C. (acetone),
- 6. 4- (5- (4-chlorophenyl) -2- (2-bromo-6-methylphenyl) imidazol-4-yl] pyridine, mp> 260 ° C. (acetone / hexane),
- 7. 4- [5- (4-chlorophenyl) -2- (2,6-diisopropylphenyl) imidazol-4-yl] pyridine, mp> 260 ° C (acetone / hexane),
- 8. 4- [5- (4-fluorophenyl) -2- (2-bromo-6-methylphenyl) imidazol-4-yl] pyridine, mp> 260 ° C. (dichloromethane),
- 9. methyl 3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzoate, mp. 228 ° C (ethyl acetate / isopropyl ether),
- 10. 4- [5- (4-chlorophenyl) -2- (2,6-dimethyl-3-nitrophenyl) imidazol-4-yl) pyridine, mp 295-298 ° C (ethyl acetate / hexane),
- 11. 4- [3- [5- (4-Chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6, -trimethylbenzyl] morpholine, m.p. 239-240 ° C ( ethyl acetate)
- 12. [3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzyl] dimethylamine, mp. 222 ° C (acetonitrile),
- 13. 1- [3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylbenzyl] -4-methylpiperazine, mp 280 ° C ( ethyl acetate)
- 14. 3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4-dimethylphenol, mp> 300 ° C. (ethanol),
- 15. 4- [5- (4-chlorophenyl) -2- (2,4,6-trimethyl-3-nitrophenyl) imidazol-4-yl] pyridine, mp. 295-299 ° C (methanol / ethyl acetate),
- 16. 3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6-trimethylphenol, mp> 300 ° C. (ethanol),
- 17. (2RS, 6RS) - and (2R, 6S) -4- [3- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] -2,4,6- trimethylbenzyl] -2,6-dimethylmorpholine, mp 163-170 ° C (ethyl acetate).
Beispiel 18Example 18
Eine Lösung von 0,2 g 4-[5-(4-Chlorphenyl)-2-(2-chlor-6-nitrophenyl)imidazol-4-yl]pyridin in 20 ml Methanol wurde in Gegenwart von 0,1 g 10%igem Palladium/Aktivkohle 2 Stunden hydriert. Der Katalysator wurde abfiltriert und die Lösung wurde zur Trockne eingedampft. Umkristallisation aus Essigsäureethylester ergab 0,1 g 3-Chlor-2-[5-(4-chlorphenyl)-4-pyridin-4-yl-imidazol-2-yl]phenylamin, Fp. 220–222°C.A solution of 0.2 g of 4- [5- (4-chlorophenyl) -2- (2-chloro-6-nitrophenyl) imidazol-4-yl] pyridine in 20 ml of methanol was in the presence of 0.1 g of 10% palladium / activated carbon Hydrogenated for 2 hours. The catalyst was filtered off and the solution became evaporated to dryness. Recrystallization from ethyl acetate gave 0.1 g of 3-chloro-2- [5- (4-chlorophenyl) -4-pyridin-4-yl-imidazol-2-yl] phenylamine, Mp 220-222 ° C.
Die Ausgangsmaterialien, die in Beispielen 1–18 verwendet wurden, deren Herstellung bis jetzt nicht beschrieben wurde, können wie nachstehend beschrieben oder in Analogie dazu hergestellt werden:
- A. Ethanonderivate (Verbindungen der Formel II) 1-(4-Chlorphenyl)-2-pyridin-4-yl-ethandion
- (i) 19,4 g 4-Pyridylmethylisocyanid wurden tropfenweise bei –5°C unter Rühren zu einer Lösung von 37,8 g Ka lium-tert-butylat in 400 ml Tetrahydrofuran gegeben. Das Gemisch wurde dann mit 23,1 g 4-Chlorbenzaldehyd behandelt und bei –5°C weitere 2 Stunden gerührt. Anschließend wurden 19,7 g Essigsäure tropfenweise bei 0°C unter Rühren zugegeben und der Feststoff wurde abfiltriert. Der Rückstand wurde an Kieselgel mit Dichlormethan/Methanol (95 : 5) als das Elutionsmittel chromatografiert und aus Dichlormethan/Hexan umkristallisiert. 25,0 g (E/Z)-N-[2-(4-Chlorphenyl)-1-pyridin-4-yl-vinyl]formamid, Fp. 155– 156°C wurden erhalten.
- (ii) Eine Lösung von 39, 0 g (E/Z)-N-[2-(4-Chlorphenyl)-1-pyridin-4-yl-vinyl]formamid in 430 ml Methanol wurde bei 0°C mit 112 ml konzentrierter Salzsäure behandelt. Das Gemisch wurde 16 Stunden bei 32–34°C gerührt. Das Gemisch wurde dann auf 0°C gekühlt und tropfenweise unter Rühren bei 0°C zu einer Lösung von 82,2 g Kaliumhydroxid in 100 ml Wasser gegeben. Der Feststoff wurde abfiltriert und aus Dichlormethan/Hexan umkristallisiert. 25,0 g 1-(4-Chlorphenyl)-2-pyridin-4-yl-ethanon, Fp. 85–86°C wurden erhalten.
- (iii) Eine Lösung von 25 g 1-(4-Chlorphenyl)-2-pyridin-4-yl-ethanon in 285 ml Dioxan wurde mit 20 g Selendioxid behandelt. Das Gemisch wurde 1 Stunde bei 100°C gerührt und filtriert. Das Lösungsmittel wurde verdampft und der Rückstand wurde in Dichlormethan gelöst. Die Lösung wurde drei Mal mit Wasser gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und eingedampft. Der Rückstand wurde in Essigsäureethylester gelöst, die Lösung wurde über Kieselgel filtriert und eingedampft, unter Gewinnung von 23,7 g 1-(4-Chlorphenyl)-2-pyridin-4-yl-ethandion, Fp. 119–120°C.
- B. Benzaldehydderivate (Verbindung der Formel III) 2-Brom-6-methylbenzaldehyd
- (i) Eine Lösung von 9,52 g (2-Brombenzyliden)phenylamin in 150 ml Essigsäure wurde mit 7, 9 g Palladium(II)acetat behandelt. Das Gemisch wurde 1 Stunde unter Rückfluss erhitzt, dann in 150 ml Wasser gegossen und drei Mal mit Dichlormethan extrahiert. Die vereinigten organischen Extrakte wurden mit Wasser gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und zur Trockne eingedampft. Der Rückstand wurde an Kieselgel mit Dichloromethan/Methanol (99 : 1) als das Elutionsmittel chromatografiert und ergab 10,3 g Bis[acetato(3-brom-2-phenyliminomethyl-phenyl)palladium](Pd-Pd), Fp. 199–200°C.
- (ii) Eine Lösung von 10,3 g Bis[acetato(3-brom-2-phenyliminomethylphenyl)palladium](Pd-Pd) in 80 ml Dichlormethan und 80 ml Aceton wurde mit 90 ml gesättigter Natriumchloridlösung unter Rühren behandelt. Nach 10 Minuten wurde der Feststoff abfiltriert und ergab 6,1 g Bis[chloro(3-brom-2-phenyliminomethylphenyl)palladium](Pd-Pd), Fp. 280–282°C.
- (iii) Eine Lösung von 6,1 g Bis[chloro(3-brom-2-phenyliminomethylphenyl)palladium](Pd-Pd) in 225 ml absolutem Benzol wurde mit 7,9 g Triphenylphosphin unter Argon behandelt. Anschließend wurde das Gemisch weitere 30 Minuten bei Raumtemperatur gerührt. 12,5 ml einer 1,6 M Lösung Methyllithium in Diethylether wurden tropfenweise bei 0°C unter Rühren zugegeben und das Gemisch wurde anschließend 1 Stunde bei Raumtemperatur gerührt. Das Gemisch wurde dann bei 0°C mit 225 ml 1 N Salzsäure behandelt, filtriert und der Feststoff wurde mit Diethylether gewaschen. Die vereinigten organischen Extrakte wurden zwei Mal mit Wasser gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und zur Trockne eingedampft. Der Rückstand wurde an Kieselgel mit Hexan/Essigsäureethylester (98 : 2) als das Elutionsmittel chromatografiert und ergab 0,7 g 2-Brom-6-methylbenzaldehyd, Fp. 48–49°C.
- A. Ethanone derivatives (compounds of formula II) 1- (4-chlorophenyl) -2-pyridin-4-yl-ethanedione
- (i) 19.4 g of 4-pyridylmethyl isocyanide was added dropwise at -5 ° C with stirring to a solution of 37.8 g of potassium tert-butoxide in 400 ml of tetrahydrofuran. The mixture was then treated with 23.1 g of 4-chlorobenzaldehyde and stirred at -5 ° C for an additional 2 hours. Then 19.7 g of acetic acid were added dropwise at 0 ° C. with stirring and the solid was filtered off. The residue was chromatographed on silica gel with dichloromethane / methanol (95: 5) as the eluent and recrystallized from dichloromethane / hexane. 25.0 g (E / Z) -N- [2- (4-chlorophenyl) -1-pyridin-4-yl-vinyl] formamide, m.p. 155- 156 ° C was obtained.
- (ii) A solution of 39.0 g of (E / Z) -N- [2- (4-chlorophenyl) -1-pyridin-4-yl-vinyl] formamide in 430 ml of methanol was dissolved at 0 ° C. with 112 ml concentrated hydrochloric acid treated. The mixture was stirred at 32-34 ° C for 16 hours. The mixture was then cooled to 0 ° C and added dropwise with stirring at 0 ° C to a solution of 82.2 g of potassium hydroxide in 100 ml of water. The solid was filtered off and recrystallized from dichloromethane / hexane. 25.0 g of 1- (4-chlorophenyl) -2-pyridin-4-yl-ethanone, mp. 85-86 ° C were obtained.
- (iii) A solution of 25 g of 1- (4-chlorophenyl) -2-pyridin-4-ylethanone in 285 ml of dioxane was treated with 20 g of selenium dioxide. The mixture was stirred at 100 ° C for 1 hour and filtered. The solvent was evaporated and the residue was dissolved in dichloromethane. The solution was washed three times with water, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in ethyl acetate, the solution was filtered through silica gel and evaporated to give 23.7 g of 1- (4-chlorophenyl) -2-pyridin-4-yl-ethanedione, mp 119-120 ° C.
- B. Benzaldehyde derivatives (compound of formula III) 2-bromo-6-methylbenzaldehyde
- (i) A solution of 9.52 g (2-bromobenzylidene) phenylamine in 150 ml acetic acid was treated with 7.7 g palladium (II) acetate. The mixture was heated under reflux for 1 hour, then poured into 150 ml of water and extracted three times with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with dichloromethane / methanol (99: 1) as the eluent to give 10.3 g of bis [acetato (3-bromo-2-phenyliminomethylphenyl) palladium] (Pd-Pd), mp 199- 200 ° C.
- (ii) A solution of 10.3 g bis [acetato (3-bromo-2-phenyliminomethylphenyl) palladium] (Pd-Pd) in 80 ml dichloromethane and 80 ml acetone was treated with 90 ml saturated sodium chloride solution with stirring. After 10 minutes the solid was filtered off to give 6.1 g of bis [chloro (3-bromo-2-phenyliminomethylphenyl) palladium] (Pd-Pd), mp 280-282 ° C.
- (iii) A solution of 6.1 g bis [chloro (3-bromo-2-phenyliminomethylphenyl) palladium] (Pd-Pd) in 225 ml absolute benzene was treated with 7.9 g triphenylphosphine under argon. The mixture was then stirred at room temperature for a further 30 minutes. 12.5 ml of a 1.6 M solution of methyl lithium in diethyl ether was added dropwise at 0 ° C. with stirring and the mixture was then stirred at room temperature for 1 hour. The mixture was then treated at 0 ° C with 225 ml of 1N hydrochloric acid, filtered and the solid was washed with diethyl ether. The combined organic extracts were washed twice with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with hexane / ethyl acetate (98: 2) as the eluent to give 0.7 g of 2-bromo-6-methylbenzaldehyde, mp 48-49 ° C.
2,6-Diisopropylbenzaldehyd2,6-Diisopropylbenzaldehyd
6,8 ml einer 1,6 M Lösung Butyllithium in Hexan wurden tropfenweise bei –78°C unter Rühren zu einer Lösung von 2,6 g 2-Brom-1,3-diisopropylbenzol in 16 ml Tetrahydrofuran gegeben. Das Gemisch wurde bei der gleichen Temperatur 30 Minuten gerührt und anschließend mit einer Lösung von 1,3 g N-Formylpiperdin in 1,5 ml Tetrahydrofuran behandelt. Anschließend wurde das Gemisch innerhalb eines Zeitraums von 6 Stunden auf Raumtemperatur erwärmen lassen. Das Gemisch wurde auf 0°C gekühlt und mit 12 ml 3 N Salzsäure behandelt. Die wässrige Lösung wurde vier Mal mit Diethylether extrahiert und die vereinigten organischen Extrakte wurden mit einer gesättigten Natriumchloridlösung gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und zur Trockne eingedampft. Der Rückstand wurde an Kieselgel mit Dichlormethan als Elutionsmittel chromatografiert und ergab 1,07 g 2,6-Diisopropylbenzaldehyd als ein Öl.6.8 ml of a 1.6 M solution of butyllithium in hexane was added dropwise at -78 ° C with stirring to a solution of 2.6 g of 2-bromo-1,3-diisopropylbenzene in 16 ml of tetrahydrofuran. The mixture was stirred at the same temperature for 30 minutes and subsequently with a solution of 1.3 g of N-formylpiperdine treated in 1.5 ml of tetrahydrofuran. The mixture was then inside allow to warm to room temperature over a period of 6 hours. The mixture was brought to 0 ° C chilled and with 12 ml of 3N hydrochloric acid treated. The watery solution was extracted four times with diethyl ether and the combined organic Extracts were saturated with a Sodium chloride solution washed, over dried anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with dichloromethane as the eluent and gave 1.07 g of 2,6-diisopropylbenzaldehyde as an oil.
2,6-Dimethyl-3-nitrobenzaldehyd2,6-dimethyl-3-nitrobenzaldehyde
2 g 2,6-Dimethylbenzaldehyd wurden bei Raumtemperatur innerhalb eines Zeitraums von 15 Minuten zu einem Gemisch von 20 ml konzentrierter Salpetersäure und 10 ml Essigsäure gegeben. Anschließend wurde das Gemisch bei Raumtemperatur 5 Minuten gerührt und auf Eiswasser gegossen. Das Gemisch wurde für weitere 5 Minuten gerührt, filtriert und der Rückstand wurde in Dichlormethan gelöst. Nach Trocknen über wasserfreiem Magnesiumsulfat wurde das Lösungsmittel verdampft. Der Rückstand wurde an Kieselgel mit Hexan/Essigsäureethylester als das Elutionsmittel chromatografiert und ergab 1,23 g 2,6-Dimethyl-3-nitrobenzaldehyd, Fp. 54–57°C (aus Hexan) und 0,33 g 2,6-Dimethyl-3,5-dinitrobenzaldehyd, Fp. 119–122°C (aus Toluol/Hexan).2 g of 2,6-dimethylbenzaldehyde were at room temperature within a period of 15 minutes to one Mixture of 20 ml of concentrated nitric acid and 10 ml of acetic acid added. Subsequently the mixture was stirred at room temperature for 5 minutes and poured on ice water. The mixture was stirred for an additional 5 minutes, filtered and the backlog was dissolved in dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The Residue was on silica gel with hexane / ethyl acetate as the eluent chromatographed and gave 1.23 g of 2,6-dimethyl-3-nitrobenzaldehyde, Mp 54-57 ° C (from hexane) and 0.33 g of 2,6-dimethyl-3,5-dinitrobenzaldehyde, mp 119-122 ° C (from toluene / hexane).
2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyd2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde
Eine Lösung von 0,98 g 3-Chlormethyl-2,4,6-trimethylbenzaldehyd in 20 ml Acetonitril wurde mit 0,87 ml Morpholin behandelt. Das Gemisch wurde 4 Stunden bei Raumtemperatur gerührt und anschließend filtriert. Das Lösungsmittel wurde verdampft und der Rückstand wurde in Essigsäureethylester gelöst. Die Lösung wurde zwei Mal mit Wasser gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und zur Trockne eingedampft. Destillation des Rückstands ergab 1,05 g 2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyd, Sdp. 150°C/0,3 Torr.A solution of 0.98 g of 3-chloromethyl-2,4,6-trimethylbenzaldehyde in 20 ml of acetonitrile was treated with 0.87 ml of morpholine. The mixture was stirred at room temperature for 4 hours and then filtered. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over anhydrous magnesium sulfate and evaporated to dryness. Distillation of the residue gave 1.05 g of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde, b.p. 150 ° C / 0.3 torr.
3-Dimethylaminomethyl-2,4,6-trimethylbenzaldehyd3-dimethylaminomethyl-2,4,6-trimethylbenzaldehyde
3-Dimethylaminomethyl-2,4,6-trimethylbenzaldehyd, Sdp. 150°C/0,3 Torr wurde in Analogie zu dem vorstehend für die Herstellung von 2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyd beschriebenen Verfahren hergestellt.3-Dimethylaminomethyl-2,4,6-trimethylbenzaldehyde, Bp 150 ° C / 0.3 Torr was analogous to that for the preparation of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde described method produced.
2,4,6-Trimethyl-3-(4-methylpiperazin-1-yl-methyl)benzaldehyd2,4,6-trimethyl-3- (4-methylpiperazin-1-yl-methyl) benzaldehyde
2,4,6-Trimethyl-3-(4-methylpiperazin-1-yl-methyl)benzaldehyd, Fp. 90°C (aus Acetonitril), wurde in Analogie zu der vorstehend für die Herstellung von 2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyd beschriebenen Weise hergestellt.2,4,6-trimethyl-3- (4-methylpiperazin-1-yl-methyl) benzaldehyde, Mp 90 ° C (from acetonitrile), was prepared analogously to that for the preparation of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde described manner.
3-Hydroxy-2,6-dimethylbenzaldehyd3-hydroxy-2,6-dimethylbenzaldehyde
- i) Eine Lösung von 2,8 g 2,6-Dimethyl-3-nitrobenzaldehyd in 150 ml Toluol wurde mit 5 ml Ethylenglycol und 20 mg p-Toluolsulfonsäure behandelt. Das Gemisch wurde 18 Stunden unter Rückfluss erhitzt, wobei das Wasser unter Verwendung eines Scheiders abgetrennt wurde. Das Gemisch wurde auf Raumtemperatur abkühlen lassen und zwei Mal mit Wasser gewaschen. Nach Trocknen über wasserfreiem Magnesiumsulfat wurde das Lösungsmittel verdampft und der kristalline Rückstand wurde aus Hexan kristallisiert. 3,0 g 2-(2,6-Dimethyl-3-nitrophenyl)-1,3-dioxolan, Fp. 69–71°C wurden erhalten.i) A solution 2.8 g of 2,6-dimethyl-3-nitrobenzaldehyde in 150 ml of toluene treated with 5 ml of ethylene glycol and 20 mg of p-toluenesulfonic acid. The mixture was refluxed for 18 hours heated, separating the water using a separator has been. The mixture was allowed to cool to room temperature and twice with Washed water. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crystalline residue was crystallized from hexane. 3.0 g of 2- (2,6-dimethyl-3-nitrophenyl) -1,3-dioxolane, Mp 69-71 ° C receive.
- ii) Eine Lösung von 2,7 g 2-(2,6-Dimethyl-3-nitrophenyl)-1,3-dioxolan in 30 ml Essigsäureethylester wurde in Gegenwart von 0,2 g Platinoxid für 45 Minuten hydriert. Der Katalysator wurde abfiltriert und die Lösung wurde zu einem kristallinen Rückstand auf konzentriert. Umkristallisation aus Hexan ergab 2,35 g 2-(3-Amino-2,6-dimethylphenyl)-1,3-dioxolan, Fp. 100–103°C.ii) A solution 2.7 g of 2- (2,6-dimethyl-3-nitrophenyl) -1,3-dioxolane in 30 ml of ethyl acetate was hydrogenated in the presence of 0.2 g of platinum oxide for 45 minutes. The Catalyst was filtered off and the solution became a crystalline Residue focused on. Recrystallization from hexane gave 2.35 g of 2- (3-amino-2,6-dimethylphenyl) -1,3-dioxolane, Mp 100-103 ° C.
- iii) Eine Lösung von 0,73 g Natriumnitrit in 2 ml Wasser wurde bei 0°C über einen Zeitraum von 15 Minuten unter Rühren zu einer Suspension von 2,0 g 2-(3-Amino-2,6-dimethylphenyl)-1,3-dioxolan in 1,9 ml of konzentrierter Schwefelsäure und 5,5 ml Wasser gegeben. Anschließend wurde das Gemisch 15 Minuten bei Raumtemperatur gerührt und dann unter Rühren innerhalb eines Zeitraums von 5 Minuten bei 110°C zu einem Gemisch von 1 ml konzentrierter Schwefelsäure und 15 ml Wasser gegeben. Das Gemisch wurde unter Rühren für eine Stunde unter Rückfluss erhitzt, dann auf Raumtemperatur abkühlen lassen, filtriert und mit Wasser gewaschen, unter Gewinnung von 1,55 g 3-Hydroxy-2,6-dimethylbenzaldehyd, Fp. 159–165°C (aus Isopropylether).iii) A solution of 0.73 g sodium nitrite in 2 ml water was at 0 ° C over a Period of 15 minutes with stirring to a suspension of 2.0 g of 2- (3-amino-2,6-dimethylphenyl) -1,3-dioxolane placed in 1.9 ml of concentrated sulfuric acid and 5.5 ml of water. Subsequently the mixture was stirred at room temperature for 15 minutes and then with stirring over a period of 5 minutes at 110 ° C to a mixture of 1 ml concentrated sulfuric acid and 15 ml of water. The mixture was stirred for one hour under reflux heated, then let cool to room temperature, filtered and with Washed water to obtain 1.55 g of 3-hydroxy-2,6-dimethylbenzaldehyde, Mp 159-165 ° C (from isopropyl ether).
3-Diethylaminomethyl-2,4,6-trimethylbenzaldehyd3-diethylaminomethyl-2,4,6-trimethylbenzaldehyde
3-Diethylaminomethyl-2,4,6-trimethylbenzaldehyd, Sdp. 200°C/0,2 Torr, wurde in Analogie zu dem für die Synthese von 2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyd beschriebenen Verfahren hergestellt.3-Diethylaminomethyl-2,4,6-trimethylbenzaldehyde, Bp 200 ° C / 0.2 Torr, was analogous to that for the Synthesis of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde described method produced.
(2RS,6RS)- und (2R,6S)-3-(2,6-Dimethylmorpholin-4-yl-methyl)-2,4,6-trimethylbenzaldehyd(2RS, 6RS) - and (2R, 6S) -3- (2,6-dimethylmorpholin-4-ylmethyl) -2,4,6-trimethylbenzaldehyde
(2RS,6RS)- und (2R,6S)-3-(2,6-Dimethylmorpholin-4-yl-methyl)-2,4,6-trimethylbenzaldehyd, Fp. 130°C (Hexan) wurde in Analogie zu dem vorstehend für die Synthese von 2,4,6-Trimethyl-3-morpholin-4-yl-methyl-benzaldehyd beschriebenen Verfahren hergestellt.(2RS, 6RS) - and (2R, 6S) -3- (2,6-dimethylmorpholin-4-yl-methyl) -2,4,6-trimethylbenzaldehyde, Mp 130 ° C (Hexane) was prepared analogously to that for the synthesis of 2,4,6-trimethyl-3-morpholin-4-yl-methyl-benzaldehyde described method produced.
Beispiele A–E erläutern die Herstellung von pharmazeutischen Zubereitungen.Examples AE illustrate the manufacture of pharmaceuticals Preparations.
Beispiel AExample A
Hartgelatinekapseln können wie
nachstehend hergestellt werden:
Das sprühgetrocknete Pulver, das auf dem Wirkstoff, Gelatine und mikrokristalliner Zellulose basierte, und das eine durchschnittliche Wirkbestandteil-Teilchengröße von < 1 μ (gemessen unter Verwendung von Autokorrelationsspektroskopie) aufwies, wird mit einer wässrigen Lösung von Natriumcarboxymethylzellulose und Natriumdioctylsulfosuccinat befeuchtet und verknetet. Die erhaltene Masse wird granuliert, getrocknet und gesiebt und das erhaltene Granulat wird mit mikrokristalliner Zellulose, Talkum und Magnesiumstearat vermischt. Das Pulver wird in Kapseln Größe 0 gefüllt.The spray dried powder that is on based on the active ingredient, gelatin and microcrystalline cellulose, and which has an average active ingredient particle size of <1 μ (measured using autocorrelation spectroscopy) with an aqueous solution of sodium carboxymethyl cellulose and sodium dioctyl sulfosuccinate moistened and kneaded. The mass obtained is granulated, dried and sieved and the granules obtained are microcrystalline Cellulose, talc and magnesium stearate mixed. The powder will filled in size 0 capsules.
Beispiel BExample B
Tabletten können wie nachstehend hergestellt
werden:
Die fein vermahlene Substanz wird mit Laktose und einem Teil der Maisstärke vermischt. Das Gemisch wird mit einer wässrigen Lösung von Povidon K30 befeuchtet und verknetet und die erhaltene Masse wird granuliert, getrocknet und gesiebt. Das Granulat wird mit der übrigen Maisstärke, Talkum und Magnesiumstearat vermischt und zu Tabletten geeigneter Größe verpresst.The finely ground substance is mixed with lactose and part of the corn starch. The mixture will with an aqueous solution of Povidon K30 moistened and kneaded and the mass obtained is granulated, dried and sieved. The granules are mixed with the remaining corn starch, talc and magnesium stearate mixed and compressed into tablets of a suitable size.
Beispiel CExample C
Weichgelatinekapseln können wie
nachstehend hergestellt werden:
10 g Verbindung I werden in 90 g Triglycerid mittlerer Kette unter Rühren und unter Inertbegasung und Schutz vor Licht gelöst. Diese Lösung wird als eine Kapselfüllmasse zu Weichgelatinekapseln, die 5 mg Wirkbestandteil enthalten, verarbeitet.10 g of compound I are in 90 g Medium chain triglyceride with stirring and with inert fumigation and protection from light solved. This solution is called a capsule filling compound processed into soft gelatin capsules containing 5 mg of active ingredient.
Beispiel DExample D
Eine Creme kann in an sich bekannter
Weise aus den nachstehend angeführten
Bestandteilen hergestellt werden:
Beispiel EExample E
Ein Gel kann in an sich bekannter
Weise aus den nachstehend angeführten
Bestandteilen hergestellt werden:
Die physikalischen Eigenschaften der Zubereitungen können durch Ändern des Verhältnisses zwischen den Hilfsstoffen in Beispielen D und E geändert werden.The physical properties of the preparations by changing of the relationship be changed between the excipients in Examples D and E.
Claims (17)
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CH376894 | 1994-12-13 | ||
PCT/EP1995/004741 WO1996018626A1 (en) | 1994-12-13 | 1995-12-01 | Imidazole derivatives as protein kinase inhibitors in particular egf-r tyrosine kinase |
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US (1) | US5959113A (en) |
EP (1) | EP0797575B1 (en) |
JP (1) | JPH10510281A (en) |
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AU (1) | AU4301096A (en) |
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DK (1) | DK0797575T3 (en) |
ES (1) | ES2208698T3 (en) |
FI (1) | FI972492A0 (en) |
PT (1) | PT797575E (en) |
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US6083949A (en) * | 1995-10-06 | 2000-07-04 | Merck & Co., Inc. | Substituted imidazoles having anti-cancer and cytokine inhibitory activity |
WO1998022109A1 (en) * | 1996-11-20 | 1998-05-28 | Merck & Co., Inc. | Triaryl substituted imidazoles as glucagon antagonists |
US5880139A (en) * | 1996-11-20 | 1999-03-09 | Merck & Co., Inc. | Triaryl substituted imidazoles as glucagon antagonists |
CA2271963A1 (en) * | 1996-11-20 | 1998-05-28 | Linda L. Chang | Triaryl substituted imidazoles, compositions containing such compounds and methods of use |
US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
WO1999064418A1 (en) * | 1998-06-05 | 1999-12-16 | Novartis Ag | Aryl pyridinyl thiazoles |
WO2000001688A1 (en) * | 1998-07-02 | 2000-01-13 | Sankyo Company, Limited | Five-membered heteroaryl compounds |
JP3850596B2 (en) * | 1999-02-25 | 2006-11-29 | 本州化学工業株式会社 | Novel partially protected trisphenols and process for their production |
WO2003024447A1 (en) * | 2001-09-20 | 2003-03-27 | Smithkline Beecham Corporation | Inhibitors of glycogen synthase kinase-3 |
US6790852B2 (en) | 2002-04-18 | 2004-09-14 | Hoffmann-La Roche Inc. | 2-(2,6-dichlorophenyl)-diarylimidazoles |
US7884120B2 (en) | 2002-08-19 | 2011-02-08 | Lorus Therapeutics Inc. | 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents |
US7144889B2 (en) | 2003-10-16 | 2006-12-05 | Hoffman-La Roche Inc. | Triarylimidazoles |
CN100436450C (en) * | 2003-10-16 | 2008-11-26 | 霍夫曼-拉罗奇有限公司 | Novel triarylimidazoles |
US7169781B2 (en) | 2003-10-17 | 2007-01-30 | Hoffmann-La Roche Inc. | Imidazole derivatives and their use as pharmaceutical agents |
JP5095216B2 (en) | 2003-11-14 | 2012-12-12 | ローラス セラピューティクス インコーポレーテッド | Arylimidazoles and their use as anticancer agents |
US8163941B2 (en) * | 2005-02-18 | 2012-04-24 | Japan Science And Technology Agency | Method for production of optically active epoxy compound, and complex used therefor and process for producing the same |
ES2473597T3 (en) | 2005-05-25 | 2014-07-07 | Lorus Therapeutics Inc. | Derivatives of 2-indolyl imidazo [4,5-d] phenanthroline and its use in cancer treatment |
JP5283872B2 (en) | 2006-09-27 | 2013-09-04 | シスメックス株式会社 | Method for evaluating growth inhibitory effect of inhibitor on tumor cell, and method for screening for compound inhibiting tumor cell growth |
AU2007305423A1 (en) * | 2006-09-28 | 2008-04-10 | Follica, Inc. | Methods, kits, and compositions for generating new hair follicles and growing hair |
US9309247B2 (en) | 2013-03-20 | 2016-04-12 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
JP6946000B2 (en) | 2013-10-04 | 2021-10-06 | アプトース バイオサイエンシーズ, インコーポレイテッド | Compositions and Methods for the Treatment of Cancer |
BR112016017993A2 (en) | 2014-02-03 | 2017-08-08 | Quadriga Biosciences Inc | BETA- SUBSTITUTED GAMMA AMINO ACIDS AND ANALOGS AS CHEMOTHERAPEUTIC AGENTS |
CA2938571C (en) | 2014-02-03 | 2020-12-22 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents |
ES2926931T3 (en) * | 2014-02-07 | 2022-10-31 | Agency Science Tech & Res | Casein kinase 1 inhibitors based on 2,4,5-tri-substituted azoles as inducers of cardiomyogenesis |
AR105592A1 (en) | 2015-08-03 | 2017-10-18 | Quadriga Biosciences Inc | b-AMINO ACIDS b-SUBSTITUTES AND ANALOGS AS CHEMOTHERAPEUTIC AGENTS AND USES OF THE SAME |
CN109212045A (en) * | 2017-07-04 | 2019-01-15 | 万全万特制药(厦门)有限公司 | The method of separating and assaying of escitalopram oxalate residual solvent and impurity |
CN111417395A (en) | 2017-10-30 | 2020-07-14 | 艾普托斯生物科学公司 | Arylimidazoles for the treatment of cancer |
CN114262298B (en) * | 2021-12-03 | 2023-09-26 | 郑州轻工业大学 | 2-bromo-4-N, N-dimethylaminoimidazole and preparation method thereof |
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US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
US3940486A (en) * | 1971-05-10 | 1976-02-24 | Ciba-Geigy Corporation | Imidazole derivatives in the treatment of pain |
CH561202A5 (en) * | 1971-05-10 | 1975-04-30 | Ciba Geigy Ag | |
MC2096A1 (en) * | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | SUBSTITUTED PYRROLES |
WO1993014082A1 (en) * | 1992-01-13 | 1993-07-22 | Smithkline Beecham Corporation | Pyridyl substituted imidazoles |
IL104369A0 (en) * | 1992-01-13 | 1993-05-13 | Smithkline Beecham Corp | Novel compounds and compositions |
CA2140440A1 (en) * | 1992-08-06 | 1994-02-17 | Ellen M. Dobrusin | 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties |
ZA945363B (en) * | 1993-07-21 | 1995-03-14 | Smithkline Beecham Corp | Novel compounds |
EP0724588B1 (en) * | 1993-09-17 | 1999-11-10 | Smithkline Beecham Corporation | Drug binding protein |
-
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- 1995-12-01 AU AU43010/96A patent/AU4301096A/en not_active Abandoned
- 1995-12-01 JP JP8518206A patent/JPH10510281A/en not_active Ceased
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CN1175252A (en) | 1998-03-04 |
CN1145623C (en) | 2004-04-14 |
MX9704263A (en) | 1997-09-30 |
BR9509998A (en) | 1997-12-30 |
DK0797575T3 (en) | 2004-02-16 |
WO1996018626A1 (en) | 1996-06-20 |
JPH10510281A (en) | 1998-10-06 |
FI972492A (en) | 1997-06-12 |
ES2208698T3 (en) | 2004-06-16 |
AR003406A1 (en) | 1998-08-05 |
CA2207404A1 (en) | 1996-06-20 |
TR199501561A2 (en) | 1996-07-21 |
EP0797575B1 (en) | 2003-10-15 |
ATE252094T1 (en) | 2003-11-15 |
CA2207404C (en) | 2004-06-29 |
PT797575E (en) | 2004-02-27 |
FI972492A0 (en) | 1997-06-12 |
EP0797575A1 (en) | 1997-10-01 |
US5959113A (en) | 1999-09-28 |
DE69531956D1 (en) | 2003-11-20 |
AU4301096A (en) | 1996-07-03 |
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